Calcineurin, also known as PP2B, is a calcium-dependent serine/threonine phosphatase that plays a pivotal role in the activation of T cells during the immune response. Calcineurin dephosphorylates the NFAT (nuclear factor of activated T cells) transcription factor, which causes a conformational change that reveals a nuclear localization signal. NFAT is then translocated to the nucleus where it induces transcription of a number of cytokines, such as interleukin-2, that orchestrate the immune response. Calcineurin is targeted by the immunosuppressant drugs, cyclosporin A and FK506. Thus, one approach to the design of immunosuppressant therapies for preventing transplant rejection and treating autoimmune disorders is the development of novel calcineurin inhibitors.
In addition to its role in activation of the immune response, calcineurin signaling has been implicated in a number of other functions, such as angiogenesis, learning and memory, schizophrenia, myocardial hypertrophy, skeletal muscle differentiation, apoptosis, intimal hyperplasia, and heart disease (Aramburu et al. (2004) EMBO reports, Vol. 5: 343-348; Bueno et al. (2002) Cardiovascular Research, Vol. 53: 806-821). In recent years, calcineurin has been identified as a mediator of calcium-dependent axon repulsion in the central nervous system induced by myelin-associated proteins. Such axon repulsion limits the ability of neuronal axons to regenerate after an injury to the spinal cord and thus prevents functional recovery. Furthermore, oligodendrocytes, which are the cells that myelinate the axons of the central nervous system, are particularly vulnerable to apoptosis following injury. Loss of these cells leads to demyelination and further loss of neuronal function (Liu et al. (1997) J. Neurosci., Vol. 17: 5395-5406). Calcineurin has been reported to promote apoptosis by activating the pro-apoptotic protein Bad through dephosphorylation (Wang et al. (1999) Science, Vol. 284:339-343) Inhibition of calcineurin after spinal cord injury in rats has been shown to result in a fewer number of apoptotic oligodendrocytes, suggesting that calcineurin is a mediator of apoptosis in these cells (Nottingham et al. (2002) Exp. Neurol., Vol. 177: 242-251). Therefore, calcineurin activation exacerbates neuronal damage caused by spinal cord injury by promoting loss of oligodendrocytes and hindering regeneration of damaged axons by mediating axon repulsion mechanisms. Thus, there is a need for the development of novel calcineurin inhibitors for treating spinal cord injury.
Other conditions, such as ischemia and multiple sclerosis, are associated with apoptosis of oligodendrocytes and demyelination of nerve fibers. Inhibition of calcineurin would be an effective therapeutic approach for treating these diseases as well. In the case of multiple sclerosis, inhibition of calcineurin would not only enhance the survival of oligodendrocytes and reduce demyelination, but also suppress the inflammatory response, which is dysfunctional in this autoimmune disorder. Given that aberrant calcineurin signaling appears to be associated with abnormal cell function and various disease states, the development of agents that regulate this phosphatase could be effective therapeutics in treating a number of conditions.